tbuckley/cabot-search huggingface dataset:
Isotretinoin Laboratory Monitoring in Acne Treatment
Authors: Eric Xia, Jane Han, Adam Faletsky, Hilary Baldwin, Katie Beleznay, Vincenzo Bettoli, Brigitte Dréno, Chee Leok Goh, Linda Stein Gold, Harald Gollnick, Maria Isabel Herane, Sewon Kang, Leon Kircik, Julianne Mann, Alexander Nast, Hazel H. Oon, Jo Ann See, Megha Tollefson, Guy Webster, Catherine Zip, Jerry Tan, Elliot B. Tapper, Diane Thiboutot, Andrea Zaenglein, John Barbieri, Arash Mostaghimi
Journal: JAMA Dermatology (2022)

Although isotretinoin may rarely be associated with laboratory abnormalities such as hypertriglyceridemia, the optimal approach to laboratory monitoring is uncertain, and there is wide variation in clinical practice.To establish a consensus for isotretinoin laboratory monitoring among a diverse, international cohort of clinical and research experts in acne.Using a modified electronic Delphi process, 4 rounds of anonymous electronic surveys were administered from 2021 to 2022. For laboratory tests reaching consensus (≥70% agreement) for inclusion, questions regarding more time-specific monitoring throughout isotretinoin therapy were asked in subsequent rounds. The participants were international board-certified dermatologist acne experts who were selected on a voluntary basis based on involvement in acne-related professional organizations and research.The primary outcome measured was whether participants could reach consensus on key isotretinoin laboratory monitoring parameters.The 22 participants from 5 continents had a mean (SD) time in practice of 23.7 (11.6) years and represented a variety of practice settings. Throughout the 4-round study, participation rates ranged from 90% to 100%. Consensus was achieved for the following: check alanine aminotransferase within a month prior to initiation (89.5%) and at peak dose (89.5%) but not monthly (76.2%) or after treatment completion (73.7%); check triglycerides within a month prior to initiation (89.5%) and at peak dose (78.9%) but not monthly (84.2%) or after treatment completion (73.7%); do not check complete blood cell count or basic metabolic panel parameters at any point during isotretinoin treatment (all >70%); do not check gamma-glutamyl transferase (78.9%), bilirubin (81.0%), albumin (72.7%), total protein (72.7%), low-density lipoprotein (73.7%), high-density lipoprotein (73.7%), or C-reactive protein (77.3%).This Delphi study identified a core set of laboratory tests that should be evaluated prior to and during treatment with isotretinoin. These results provide valuable data to guide clinical practice and clinical guideline development to optimize laboratory monitoring in patients treated with isotretinoin.
Abstract 1302: Priming tumors using pH sensitizers potentiates the anti-tumor T cell response induced by immune checkpoint blockade therapy
Authors: Renee Chin, Jorge de la Cerda, William Schuler, Mark D. Pagel
Journal: Cancer Research (2022)

Abstract While immune checkpoint blockade (ICB) treatments such as nivolumab and ipilimumab have spelled hope for many cancer patients, not all patients benefit from this form of therapy. One mechanism by which tumors suppress the anti-tumor T cell activity that results from ICB is through decreasing extracellular tumor pH (pHe), a function inherent to tumor cells due to the Warburg effect. We thus hypothesize that increasing pHe prior to ICB therapy potentiates the T cell-mediated anti-tumor effect of ICB treatment. To undergo this study, we first screened a panel of six inhibitors termed pH sensitizers, and found that esomeprazole significantly reduced the proton efflux rate (PER) of 4T1, but not B16-F10 cells. Furthermore, esomeprazole did not significantly reduce cell viability of either 4T1 or B16-F10 cells, and did not significantly inhibit T cell activity. Moving forward, our next objectives are to investigate the effects of esomeprazole and the combination of esomeprazole and ICB on tumor-bearing mice. Assessment of the tumor growth in response to esomeprazole and ICB and ex vivo interrogation of the immune cell infiltrate into the tumors will elucidate the efficacy of the treatment combination in terms of tumor control and anti-tumor immunity. Modification of pHe by esomeprazole will be examined by acidoCEST MRI, which will also provide insights as to the ideal pHe parameters for optimal ICB therapy in patients. Citation Format: Renee Chin, Jorge de la Cerda, William Schuler, Mark D. Pagel. Priming tumors using pH sensitizers potentiates the anti-tumor T cell response induced by immune checkpoint blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1302.
Abstract 2630: Heterogeneity inducible tumor stem cells relate distant metastasis and the treatment resistance
Authors: Norikatsu Miyoshi, Shiki Fujino, Yuki Sekido, Tsuyoshi Hata, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, HIrofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi
Journal: Cancer Research (2022)

Abstract Regarding metastatic potential of cancer cells and the refractory status, regulatory and epigenetic factors underlie the cancer treatment resistance by inducing cellular heterogeneity. Circulating tumor cells (CTCs) and their stemness are critical for metastases formation associated with poor survival rates. In colorectal cancer (CRC), several stem-cell markers, such as CD44v9 and LGR5, the positive cells cause intertumoral heterogeneity and promote refractory potential. However, the mastermind of the cells which is critical for the treatment resistance remains unknown. Here, we aimed to identify the mechanisms of the treatment resistance of the CRC by focusing on typical stem cells. We selected several stem cell-related genes such as pluripotency related genes, based on the expression profile analysis of CRC patients along with drug susceptibility assays using patient-derived organoids. Despite the small number of cancer stem cells, the single cell produced heterogeneous cell populations in vitro and in vivo, expressing various differentiation and stem biomarkers, and confirmed by the knockdown analysis. Single-cell trajectory analysis suggested that heterogeneous populations including cancer stem and some persister cells were derived from the stem cells following administration of anti-cancer drugs. Furthermore, the stem cells formed heterogeneous liver metastases at a high rate, and these unique cells were observed in the bloodstream of CRC patients. This present study unveils a mechanism of CRC treatment resistance and highlights the potential of stem marker-expressing cells as CTCs. Citation Format: Norikatsu Miyoshi, Shiki Fujino, Yuki Sekido, Tsuyoshi Hata, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, HIrofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi. Heterogeneity inducible tumor stem cells relate distant metastasis and the treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2630.
Abstract 5847: Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity
Authors: Rakefet Ruth Ben-Yishay, Naama Herman, Vered Noy, Eyal Mor, Aiham Mansur, Dana Ishay-Ronen
Journal: Cancer Research (2022)

Abstract Background: Epithelial-mesenchymal transition (EMT) in breast cancer drives tumor invasion, metastasis and drug resistance. BRCA1 mutation carriers have a high risk for developing aggressive basal-like triple-negative breast cancers with EMT characteristics. It has been described that normal mammary epithelium of BRCA1-mutation carriers is comprised of aberrant luminal progenitor cell population resembling basal-like breast cancer cells. Yet, the role of BRCA1 in regulating epithelial cell plasticity in normal mammary gland remains largely obscure. Aim: Here, we used patient-derived normal and cancer organoid cultures from BRCA1-mutation carriers and noncarriers, to examine the effect of the BRCA1 mutation background on epithelial cell plasticity and the susceptibility to EMT. Methods and results: Mammary organoids were established from normal or cancer mammary tissues obtained from consenting patients undergoing lumpectomy or mastectomy. Isolated cells were plated in adherent basement membrane extract (BME) drops and overlaid with optimized organoid culture medium. EMT regulation in breast cancer is usually studied using cell lines and murine models. To determine the possibility to study EMT on patient-derived organoids, organoid culture media was optimized and established organoids were exposed to TGFβ to induce EMT. Morphological and phenotypic alterations were characterized using immunolabeling and visualization with confocal microscopy. Breast cancer organoids induced with TGFβ demonstrated EMT-like changes including the downregulation of E-Cadherin and upregulation of N-Cadherin. Moreover, breast cancer organoids showed typical cytoskeleton rearrangements. Here, the transformation from cortical actin into stress fibers formed in dedifferentiated mesenchymal cells, was visualized with actin staining. However, normal mammary organoids behaved differently. The cytoskeleton of BRCA-wild type (noncarriers) normal mammary organoids was not affected by the treatment. Curiously, normal mammary organoids derived from BRCA1-mutation carriers demonstrated EMT like changes upon exposure to TGFβ. To further determine mechanisms facilitating cell plasticity in BRCA1-mutation carriers, single cell RNA sequencing analysis on BRACA1-mutation carriers and noncarriers derived organoids is ongoing. Conclusion: The results suggest that BRCA1 germline mutation predisposes normal mammary epithelium dedifferentiation due to increased susceptibility to EMT. Citation Format: Rakefet Ruth Ben-Yishay, Naama Herman, Vered Noy, Eyal Mor, Aiham Mansur, Dana Ishay-Ronen. Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5847.
Abstract 75: Highly multiplexed <i>EGFR</i> mutation detection from liquid biopsy samples using the 6-color Crystal Digital PCR™
Authors: Cécile Jovelet, Myrtille Remy, Noémie Pata-Merci, Damien Vasseur, Ludovic Lacroix, Claudia Labrador-Rached, Allison C. Mallory
Journal: Cancer Research (2022)

Abstract Liquid biopsies are a minimally invasive sampling approach to overcome the heterogeneity of tumors and represent a valuable source of circulating tumor DNA (ctDNA) for oncological biomarker analysis. ctDNA measurements require a highly sensitive and reliable detection technology to quantify often low-level genetic aberrations within a high background of wild-type sequences. Digital PCR emerged as a powerful technology for the next-generation analysis of liquid biopsies. Stilla Technologies' 6-color naica® system is an ultrasensitive, easy-to-use digital PCR platform capable of simultaneously and precisely quantifying high numbers of biomarkers in a single reaction. Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide. Epidermal growth factor receptor (EGFR) is frequently mutated in NSCLC. A handful of anti-EGFR Tyrosine Kinase Inhibitor therapies are approved by the FDA; however, most patients develop resistance over time to these treatments. Both monitoring primary EGFR mutations to predict treatment response and precociously detecting resistance mutations to adapt treatments promptly through ctDNA analysis stand to improve the effectiveness of NSCLC patient management. Stilla has developed a highly multiplexed 6-color Crystal Digital PCR EGFR kit detecting more than 90% of EGFR mutations described in NSCLC from ctDNA. The assay detects 32 common and rare somatic EGFR mutations in exons 18, 19, 20, and 21, including both activating and resistant mutations. In this work, we evaluated the sensitivity, precision and specificity of the EGFR 6-color Crystal Digital PCR assay highly specific and sensitive for the detection of EGFR mutations, with a Limit of Detection in a high background of wild-type DNA ranging from 0.30 to 0.46 cp/μL (with observed MAFs ranging from 0.06 to 0.09%). Moreover, a high concordance was observed between those EGFR results obtained for NSCLC ctDNA samples using 6-color Crystal Digital PCR and other technologies. With a rapid time to results and straightforward ctDNA analysis workflow, Crystal Digital PCR on the naica system promises ultrasensitive, highly multiplexed 6-color mutation detection, maximizing the information obtained from precious samples. Citation Format: Cécile Jovelet, Myrtille Remy, Noémie Pata-Merci, Damien Vasseur, Ludovic Lacroix, Claudia Labrador-Rached, Allison C. Mallory. Highly multiplexed EGFR mutation detection from liquid biopsy samples using the 6-color Crystal Digital PCR™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 75.
Abstract 4031: PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer
Authors: Samyuktha Suresh, Solène Huard, Fariba Némati, Rayan Dakroub, André Nicolas, Didier Meseure, Didier Decaudin, Sergio Roman-Roman, Thierry Dubois
Journal: Cancer Research (2022)

Abstract Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. We found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve the existing treatments for TNBC patients. Citation Format: Samyuktha Suresh, Solène Huard, Fariba Némati, Rayan Dakroub, André Nicolas, Didier Meseure, Didier Decaudin, Sergio Roman-Roman, Thierry Dubois. PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4031.
Brain Health in Patients With Atrial Fibrillation—Another Reason to Quit Smoking Now
Authors: T. Jared Bunch
Journal: JAMA Network Open (2022)

Hui-Jin Lee, MD; So-Ryoung Lee, MD, PhD; Eue-Keun Choi, MD, PhD; Sang-Hyun Park, MD; Jae-Wook Chung, MD; Jung-Min Choi, MD; Min-Ju Han, MD; Jin-Hyung Jung, MS; Kyung-Do Han, PhD; Seil Oh, MD, PhD; Gregory Y. H. Lip, MD
Abstract 3902: TRIM33 interacts with HSF1 in osteosarcoma development
Authors: Morgane Lallier, Robel Tefaye, Brice Moukengué, Céline Charrier, Rose-Anne Thepault, Benedicte Brounais-Le Royer, Marc Baud'huin, Franck Verrecchia, Benjamin Ory, François Lamoureux
Journal: Cancer Research (2022)

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor in oncopediatrics. Despite therapeutic advances, the 5-year survival rate is 30% in bad responders to treatment or when pulmonary metastases are present at diagnosis. It is therefore urgent to better understand the molecular mechanisms involved in the development of OS in order to identify new therapeutic targets. As a major player in the stress response, it has recently been shown that the transcription factor HSF1 coordonates a stress-independent transcriptional program involving it in many pro-tumor biological processes in different cancers. A better understanding of the mechanisms by which HSF1 activity participates in tumor development is therefore essential to consider its therapeutic targeting. The co-partners of HSF1 to DNA, by modulating its transcriptional activity, could explain its pleiotropic effects. Based on this hypothesis, TRIM33 was identified by RIME. TRIM33 is known as a transcriptional cofactor and its involvement in various cancers. In this context, our objective is to study the interaction between TRIM33 and HSF1, their common genomic localization and to investigate the involvement of TRIM33 in the development of OS. Our results show that TRIM33 and HSF1 co-localize in the nucleus in OS TMA and by immuno-fluorescence in tumor cells and preclinical models. Furthermore, we observed by chIP-seq that TRIM33 and HSF1 share common DNA binding sites. Finally, our preliminary results show that TRIM33 invalidation by RNA interference in OS cell lines decreases tumor cell proliferation. Thus, in view of its role as a DNA partner of HSF1, TRIM33 is an interesting therapeutic target in OS. This work was supported by la Fédération Enfants et Santé, la SFCE et La ligue Contre le Cancer (comités 44, 49) Citation Format: Morgane Lallier, Robel Tefaye, Brice Moukengué, Céline Charrier, Rose-Anne Thepault, Benedicte Brounais-Le Royer, Marc Baud'huin, Franck Verrecchia, Benjamin Ory, François Lamoureux. TRIM33 interacts with HSF1 in osteosarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3902.
Abstract 1862: Naphthoquinone analogues inhibit Wnt/β-catenin signaling and colorectal cancer tumorigenesis
Authors: Rosalie G. Hoyle, Andrew Morris, Piyusha Pagare, Shadid Uz Zaman, Zhikun Ma, Yan Zhang, Jiong Li
Journal: Cancer Research (2022)

Abstract In this study, we performed a structure-activity-relationship study of seven previously identified chloro-naphthoquinone analogs and evaluated their abilities to inhibit the Wnt/β-catenin signaling pathway. The Wnt/β-catenin signaling pathway plays essential roles in colorectal cancer (CRC) initiation, proliferation, and development. While targeting the Wnt/β-catenin pathway has been validated as a very promising approach for CRC treatment, developing a therapeutic for inhibition of this elusive pathway has been very challenging for researchers. Of the seven chloro-naphthoquinone analogues, we found that two compounds, Compound 3 and Compound 6, significantly inhibited Wnt target gene transcription and Wnt-induced colorectal tumorigenesis in vitro. Chromatin immunoprecipitation binding assays and computational modeling analysis revealed that Compound 3 and Compound 6 inhibit the Wnt/β-catenin pathway through disruption of the TCF4-DNA binding, a crucial step for the activation of the Wnt/β-catenin signaling pathway. Lastly, using a patient-derived organoid model and xenograft mouse model, we showed that these compounds inhibit CRC tumorigenesis. Taken together, this study demonstrates a novel mechanism of action for these chloro-naphthoquinone analogs, which can be further explored in future drug design and discovery efforts for small molecules targeting the TCF family proteins for inhibition of the Wnt/β-catenin signaling pathway. Citation Format: Rosalie G. Hoyle, Andrew Morris, Piyusha Pagare, Shadid Uz Zaman, Zhikun Ma, Yan Zhang, Jiong Li. Naphthoquinone analogues inhibit Wnt/β-catenin signaling and colorectal cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1862.
Abstract 6300: Cyprohepatdine, an anti-histamine and epigenetic modifier, reverses epigenetic silencing of the tumor suppressor IRF6 in urothelial carcinoma
Authors: Michael W.Y. Chan, Pie-Che Chen, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Hon-Yi Lin, Yeong-Chin Jou, Cheng-Huang Shen
Journal: Cancer Research (2022)

Abstract Urothelial carcinoma (UC) is the most common malignancy of the urinary system. We have previously demonstrated that cyproheptadine (CPH), an anti-histamine, inhibited UC tumor growth in vitro and in vivo. However, the exact mechanism of how CPH inhibited tumor growth is not fully understood. In this study, we performed RNA-Seq in control BFTC905 UC cells and cells treated with CPH. The results showed that several genes, including IRF6 (interferon regulator factor 6), showing differential upregulation after CPH treatment. Real-time RT-PCR confirmed the restoration of IRF6 expression in a panel of UC cell lines treated with CPH. Similar to 5azaDC, bisulphite pyrosequencing found that CPH could decrease promoter methylation of IRF6 in UC cell lines. Interestingly, CPH could also increase total mono-methylation of H3K4 and acetylation of H3K27. Functional studies found that ectopic expression of IRF6 suppressed UC tumor growth in vitro and in vivo. Clinical studies also found that high-grade UC patient tissue samples has significantly higher IRF6 methylation than low-grade tumor samples. Taken together, our results suggested that CPH may be a novel epigenetic modifier exhibiting both DNMTi and HDACi activities in UC. The therapeutic potential of CPH in the treatment of UC deserves further investigation. Citation Format: Michael W.Y. Chan, Pie-Che Chen, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Hon-Yi Lin, Yeong-Chin Jou, Cheng-Huang Shen. Cyprohepatdine, an anti-histamine and epigenetic modifier, reverses epigenetic silencing of the tumor suppressor IRF6 in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6300.